Film-Shaped Mucoadhesive Administration Forms For Administering Cannabis Agents

ABSTRACT

A film-shaped, mucoadhesive administration form having a content of at least one active agent. The active agent is a cannabis agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/EP03/04807, filed on May 8, 2003, which claimspriority of German application number 102 26 494.5, filed on Jun. 14,2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to film-shaped, mucoadhesiveadministration forms which have a content of cannabis agents and whichare suitable for administration of cannabis agents for therapeuticpurposes. The invention further relates to the use of the saidadministration forms for treating conditions of disease in humans oranimals.

2. Description of the Prior Art

The components of the Indian hemp plant (Cannabis sativa L.) havenumerous pharmacological effects, of which the psychotropic effect ismost widely known. Apart from this, cannabis components also haveanti-emetic, anticonvulsive, muscle-relaxing, analgesic, sedative andappetite-increasing effects.

Because of the psychotropic or euphorizing effect and the dependencypotential associated therewith, the therapeutic application of cannabiscomponents is subject to severe restrictions.

It has long been known that cannabis components can be used beneficiallyfor treating insomnia, neuralgias and painful rheumatism, as well asgastric and intestinal disorders. A favourable therapeutic effect ofcannabis components has furthermore been observed for the followingindications:

Conditions of pain in cases of carcinosis and as a result ofchemotherapy; conditions of pain and “wasting” syndrome in connectionwith AIDS; nausea and vomiting as side effects of chemotherapy as wellas in connection with AIDS or hepatitis; neuropathic pain; anorexia orcachexia, especially in connection with AIDS or carcinosis in theadvanced stages.

A favourable therapeutic effect of cannabis components has also beenobserved in connection with paralytic symptoms in connection withmultiple sclerosis or traumatic transverse lesions; dystonic motordisturbance; bronchial asthma; epileptic attacks or generalizedepilepsia; withdrawal symptoms in connection with alcohol dependence,benzodiazepine dependence and opiate dependence; Parkinson's disease;dementia, especially Morbus Alzheimer; nausea; arthritis; glaucoma;migraine; and dysmenorrhoea.

At present, only the synthetically produced cannabis agent R-(6a,10a)-Δ-9-tetrahydrocannabinol (Dronabinol) is marketable. This isomer oftetrahydrocannabinol (THC) is sold under the product name Marinol. Thismedicament is administered orally in the form of capsules. Marinol isused for treating severe loss of weight in AIDS patients and cancerpatients who, as a result of chemotherapy, suffer from heavy vomiting.

Apart from the aforementioned THC isomer, cannabis extracts and cannabisoils for therapeutic treatment purposes are also suitable. Applicationis usually effected via the oral route, e.g. in the form of capsules.

Cannabis extracts contain as pharmacologically active ingredientstetrahydrocannabinol (predominantly Δ-9-tetrahydrocannabinol, in smallproportion: Δ-8-tetrahydrocannabinol), cannabidiol, cannabinol andcannabichromen. These active agents are also called cannabinoids (seethe list “The Merck Index”, 12th ed., 1996, page 285, No. 1794, as wellas page 1573, No. 9349).

Oral administration of cannabis agents, especially of R-(6a,10a)-Δ-9-tetrahydrocannabinol, in the form of capsules, tablets, pillsor other solid, oral administration forms, or in the form of orallyadministered liquid preparations is disadvantageous for a variety ofreasons:

-   -   Since on use of the aforementioned administration forms, the        absorption of the active agent takes place in the        gastrointestinal tract, the time of onset of action is delayed.        This is disadvantageous especially with respect to the        indications mentioned, which generally require a quick onset of        action (e.g. pain therapy).    -   Cannabis agents are at least partially degraded and inactivated        during the passage through the stomach and intestines under the        influence of acid and enzymes, so that only part of the        administered dose is absorbed and is systemically available.    -   In this connection, unwanted plasma peak values may occur which        are frequently the cause of side effects.    -   In addition, after oral administration a significant portion of        the active substance is already metabolised during the first        passage through the liver (“first pass effect”).

These disadvantages are particularly important with respect to theacceptance with which these medicaments are met in the above indicatedindications. With the mentioned oral administration forms, it is alsodisadvantageous that patients, in a particular given situation, regardthe extended retention, e.g. of a tablet or capsule (filled with an oilysolution) in the mouth as particularly unpleasant.

SUMMARY OF THE INVENTION

It is therefore the object of the present invention to provide anadministration form for the administration of cannabis agents which isfree from the above-described disadvantages and which stands out inparticular for its improved acceptance and compliance, as well as foradvantageous pharmacokinetic properties, especially for a rapid onset ofaction.

This object is achieved by a film-shaped, mucoadhesive administrationform having a content of at least one active agent from the group of thecannabis agents, such as a cannabis extract or a cannabis oil.

The object is furthermore achieved by the use of the film-shaped,mucoadhesive administration forms according to the invention in thetreatment of diseases and symptoms.

DETAILED DESCRIPTION OF THE INVENTION

The administration forms according to the invention are applied, in theform of thin, small flat pieces or wafer-shaped objects (“wafers”), tothe oral mucosa where they adhere because of their mucoadhesiveproperties. Application to the oral mucosa is sublingual or buccal.Furthermore, other mucosal surfaces may also be taken into considerationas an application site, e.g. the nasal mucosa.

During the period of application, the cannabis agent(s) contained in theadministration form are released into the surrounding saliva and aresubsequently absorbed by the oral mucosa (i.e. transmucosally). In thecontact area of the application surface, the active agent may also bereleased directly from the administration form to the oral mucosa.During application, the administration form absorbs saliva and theactive substance contained therein gets to the outside by diffusion.

It is advantageous in this connection that the active agent is releasedinto the saliva after only a short time lag, so that the saliva-activeagent mixture immediately reaches all areas of the oral mucosa, where itcan be absorbed. The amount of saliva in which the released active agentis dissolved or dispersed per unit of time is relatively small and thereoccurs no hypersalivation so that swallowing of the active agent(involving the mentioned disadvantages of gastrointestinal absorption)is largely excluded.

Since active agent absorption takes place by circumventing thegastrointestinal route, the above-described disadvantages (delayed onsetof action, “first pass effect”) of other oral administration forms (e.g.tablets) are avoided.

With the administration forms of the invention, compliance is increasedas well, since application requires no special discipline. Due to theirsmall layer thickness the application of the film-shaped administrationforms of the present invention is generally not unpleasant by thetreated persons.

According to one embodiment, the administration forms of the inventioncomprise a polymer matrix which serves as an active agent reservoir andhas mucoadhesive properties. At least one layer or at least one surfaceof the administration form possesses mucoadhesive properties. Theadministration form may consist of one single layer or comprise aplurality of layers. In the case of a multilayer structure, at least oneof the layers contains active agent(s).

In the simplest case, an administration form is made up of amucoadhesive, preferably monolayer polymer matrix containing one or morecannabis agents. The active agent(s) may be present in theadministration form in dissolved, dispersed or emulsified form.

The polymer matrix contains one or more polymers which are water-solubleand/or swellable in an aqueous media. By selecting such polymers, it ispossible to influence the mucoadhesive properties and the releasebehaviour.

Polymers of the following group are particularly suitable aswater-soluble or swellable polymers: starch and starch derivatives,dextran; cellulose derivatives, such as carboxymethyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, sodium carboxymethylcellulose, ethyl cellulose or propyl cellulose; polyacrylic acid,polyacrylates, polyvinyl pyrrolidones, polyethylene oxide polymers,polyacrylamides, polyethylene glycol, gelatine, collagen, alginates,pectins, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan,galactomannan, agar-agar, agarose, carrageenan, and natural gums.

The polymer portion is 5 to 95%-wt, especially 15 to 75%-wt, relative tothe dry matter of the administration form.

According to one embodiment, the administration forms according to theinvention contain a cannabis extract or a cannabis oil, in an amount of0.5 to 50%-wt, especially in an amount of 1 to 30%-wt. Processes for themanufacture of pharmaceutically acceptable cannabis extracts or cannabisoils are known to those skilled in the art.

The invention furthermore comprises administration forms of thementioned type containing at least one cannabinoid active agent from thegroup consisting of tetrahydrocannabinol, cannabinol, cannabidiol, andcannabichromen. Tetrahydrocannabinol, especiallyR-(6a,10a)-Δ-9-tetrahydrocannabinol, is also a suitable active agent.The cannabinoid active agents may be of natural, partially synthetic orsynthetic origin.

The active substance content amounts to 0.1 to 20%-wt, especiallypreferably 0.5 to 10%-wt, relative to the dry matter of anadministration form.

An individual administration form contains 0.5 to 20 mg, especiallypreferably 1 to 10 mg of active agent, e.g. tetrahydrocannabinol.

Optionally, the administration forms according to the invention maycontain one or more additives from the following groups: fillers,colourants, flavourings, aromatics, odorous substances, emulsifiers,plasticizers, sweeteners, preservatives, permeation-enhancingsubstances, pH regulators and antioxidants. Substances suitable for thispurpose are in principle known to the skilled artisan.

The administration form according to the present invention can alsoinclude flavourings, odorous substances and aromatics, either alone orin combination. It is, for example, possible to improve the impressionof the taste by adding a refreshing flavouring (e.g. menthol,eucalyptol). This simultaneously enables inconspicuous intake of themedicament as it smells like a usual refreshment sweet. It additionallycontributes to improving compliance.

Especially suitable are, for example, flavourings and aromatics from thegroup comprising menthol, eucalyptol, limonene, phenyl ethanol,camphene, pinene, seasoning aromatics such as n-butyl phthalide orcineol, as well as eucalyptus oil and thyme oil, methyl salicylate,turpentine oil, camomile oil, ethyl vanillin, 6-methyl coumarin,citronellol, and acetic acid n-butyl ester.

The inventive administration forms containing cannabis agents arefilm-shaped, i.e. of a thin and flat shape, for example in the form ofthin, small flat pieces or small wafers. These film-shaped plates may beof various geometric shapes, e.g. circular, ellipsoid or elongated.

The thickness of the administration form amounts to 0.01 to 2 mm; or inthe range of 0.05 to 0.5 mm. To avoid a foreign body sensation, thelayer thickness should be as small as possible (such as smaller than 0.2mm).

To achieve special effects, the administration forms according to theinvention may have a bilayer or monolayer structure. The individuallayers may differ in terms of one or more of the following parameters:polymer composition, active substance content, active substanceconcentration, content of additives.

Due to the already mentioned properties, the cannabis agents-containingadministration forms according to the invention can be advantageouslyemployed in the treatment of diseases or symptoms, especially in casesof conditions of pain in cases of carcinosis and as a result ofchemotherapy; conditions of pain and “wasting” syndrome in connectionwith AIDS; nausea and vomiting, especially nausea and vomiting as sideeffects of a chemotherapy as well as in connection with AIDS orhepatitis; neuropathic pain; anorexia or cachexia, especially inconnection with AIDS or carcinosis in the advanced stages; paralyticsymptoms in connection with multiple sclerosis or traumatic transverselesions; dystonic motor disturbance; bronchial asthma; epileptic attacksor generalized epilepsia; withdrawal symptoms in connection with alcoholdependence, benzodiazepine dependence and opiate dependence; Parkinson'sdisease; dementia, especially Alzheimer's disease; nausea; arthritis;glaucoma; migraine; dysmenorrhoea.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. A film-shaped, mucoadhesive administration form containing a cannabisagent selected from the group consisting of cannabis extract andcannabis oil.
 2. The administration form according to claim 1, whereinsaid administration form comprises a polymer matrix, said polymer matrixbeing an active substance reservoir and having mucoadhesive properties.3. The administration form according to claim 2, wherein said polymermatrix contains at least one polymer being water-soluble and/orswellable in an aqueous media, said at least one polymer is selectedfrom the group consisting of starch and starch derivatives, dextran,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethylcellulose, sodium carboxymethyl cellulose, ethyl cellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinyl pyrrolidones,polyethylene oxide polymers, polyacrylamides, polyethylene glycol,gelatine, collagen, alginates, pectins, pullulan, tragacanth, chitosan,alginic acid, arabinogalactan, galactomannan, agar-agar, agarose,carrageenan and natural gums, and wherein said administration formcomprises said at least one polymer at a portion of 5 to 95%-wt.
 4. Theadministration form according to claim 1, wherein said administrationform contains said cannabis agent selected from the group consisting ofcannabis extract and cannabis oil in an amount of 0.5 to 50%-wt.
 5. Theadministration form according to claim 1, wherein said administrationform further contains at least one substance selected from the groupconsisting of flavourings, odorous substances and aromatics.
 6. Theadministration form according to claim 1, wherein the layer thickness is0.01 to 2 mm.
 7. The administration form according to claim 1, whereinsaid administration form further contains at least one inactiveingredient selected from the group consisting of fillers, colourants,emulsifiers, plasticizers, sweeteners, preservatives, pH regulators,permeation-enhancing substances, and antioxidants.
 8. The administrationform according to claim 1, wherein said administration form has amultilayer structure with at least one layer having an active agentcontent.
 9. A method of treating conditions of pain in cases ofcarcinosis and as a result of chemotherapy; conditions of pain and“wasting” syndrome in connection with AIDS; nausea and vomiting,especially nausea and vomiting as side effects of a chemotherapy as wellas in connection with AIDS or hepatitis; neuropathic pain; anorexia orcachexia, especially in connection with AIDS or carcinosis in theadvanced stages; paralytic symptoms in connection with multiplesclerosis or traumatic transverse lesions; dystonic motor disturbance;bronchial asthma; epileptic attacks or generalized epilepsia; withdrawalsymptoms in connection with alcohol dependence, benzodiazepinedependence and opiate dependence; Parkinson's disease; dementia,especially Alzheimer's disease; arthritis; glaucoma; migraine;dysmenorrhoea, said method comprising the step of: administering afilm-shaped, mucoadhesive administration form containing a cannabisagent selected from the group consisting of cannabis extract andcannabis oil to an inflicted person.
 10. A method of treating conditionsof pain in cases of carcinosis and as a result of chemotherapy;conditions of pain and “wasting” syndrome in connection with AIDS;nausea and vomiting, especially nausea and vomiting as side effects of achemotherapy as well as in connection with AIDS or hepatitis;neuropathic pain; anorexia or cachexia, especially in connection withAIDS or carcinosis in the advanced stages; paralytic symptoms inconnection with multiple sclerosis or traumatic transverse lesions;dystonic motor disturbance; bronchial asthma; epileptic attacks orgeneralized epilepsia; withdrawal symptoms in connection with alcoholdependence, benzodiazepine dependence and opiate dependence; Parkinson'sdisease; dementia, especially Alzheimer's disease; arthritis; glaucoma;migraine; dysmenorrhoea, said method comprising the step of:administering a film-shaped, mucoadhesive administration form to anafflicted person, said administration form containing a cannabinoidactive agent selected from the group of active agents consisting oftetrahydrocannabinol, cannabinol, cannabidiol and cannabichromen. 11.The method according to claim 9, wherein the administration form is afilm-shaped, mucoadhesive administration form containing a cannabisagent selected from the group consisting of cannabis extract andcannabis oil, and wherein said administration form comprises a polymermatrix, said polymer matrix being an active substance reservoir andhaving mucoadhesive properties.
 12. The method according to claim 9,wherein the treatment is effected by application of the administrationform to the oral mucosa.
 13. A medicinal product for treating conditionsof pain in cases of carcinosis and as a result of chemotherapy;conditions of pain and “wasting” syndrome in connection with AIDS;nausea and vomiting, especially nausea and vomiting as side effects of achemotherapy as well as in connection with AIDS or hepatitis;neuropathic pain; anorexia or cachexia, especially in connection withAIDS or carcinosis in the advanced stages; paralytic symptoms inconnection with multiple sclerosis or traumatic transverse lesions;dystonic motor disturbance; bronchial asthma; epileptic attacks orgeneralized epilepsia; withdrawal symptoms in connection with alcoholdependence, benzodiazepine dependence and opiate dependence; Parkinson'sdisease; dementia, especially Alzheimer's disease; arthritis; glaucoma;migraine; dysmenorrhoea, said medicinal product comprising afilm-shaped, muco-adhesive administration form containing a cannabisagent selected from the group consisting of cannabis extract andcannabis oil.
 14. A medicinal product for treating conditions of pain incases of carcinosis and as a result of chemotherapy; conditions of painand “wasting” syndrome in connection with AIDS; nausea and vomiting,especially nausea and vomiting as side effects of a chemotherapy as wellas in connection with AIDS or hepatitis; neuropathic pain; anorexia orcachexia, especially in connection with AIDS or carcinosis in theadvanced stages; paralytic symptoms in connection with multiplesclerosis or traumatic transverse lesions; dystonic motor disturbance;bronchial asthma; epileptic attacks or generalized epilepsia; withdrawalsymptoms in connection with alcohol dependence, benzodiazepinedependence and opiate dependence; Parkinson's disease; dementia,especially Alzheimer's disease; arthritis; glaucoma; migraine;dysmenorrhoea, said medicinal product comprising a film-shaped,mucoadhesive administration form containing a cannabinoid active agentselected from the group of active agents consisting oftetrahydrocannabinol, cannabinol, cannabidiol and cannabichromen. 15.The medicinal product according to claim 14, wherein the administrationform is a film-shaped, mucoadhesive administration form containing acannabis agent selected from the group consisting of cannabis extractand cannabis oil, and wherein said administration form comprises apolymer matrix, said polymer matrix being an active substance reservoirand having mucoadhesive properties, said reservoir containing saidcannabis extract or cannabis oil.
 16. The medicinal product according toclaim 13, wherein the administration form is an administration form forapplication on the oral mucosa.
 17. The administration form according toclaim 3, wherein said administration form comprises said polymer at aportion of 15 to 75%-wt.
 18. The administration form according to claim4, wherein said administration form contains said cannabis agentselected from the group consisting of cannabis extract and cannabis oilin an amount of 1 to 30%-wt.
 19. The administration form according toclaim 5, wherein said flavourings, odorous substances and aromatics areselected from the group consisting of menthol, eucalyptol, limonene,phenyl ethanol, camphene, pinene, n-butyl phthalide, cineol, eucalyptusoil, thyme oil, methyl salicylate, turpentine oil, camomile oil, ethylvanillin, 6-methyl coumarin, citronellol, and acetic acid n-butyl ester.20. (canceled)
 21. The administration form according to claim 6, whereinthe layer thickness is 0.05 to 0.5 mm.
 22. The method according claim12, wherein the application of the administration form to the oralmucosa is selected from the group consisting of sublingual applicationand buccal application.
 23. The method according to claim 10, whereinthe administration form is a film-shaped, mucoadhesive administrationform containing a cannabinoid agent selected from the group consistingof tetrahydrocannabinol, cannabinol, cannabidiol and cannabichromen andwherein said administration form comprises a polymer matrix, saidpolymer matrix being an active substance reservoir and havingmucoadhesive properties.
 24. The method according to claim 10, whereinthe treatment is effected by application of the administration form tothe oral mucosa.
 25. The method according claim 24, wherein theapplication of the administration form to the oral mucosa is selectedfrom the group consisting of sublingual application and buccalapplication.
 26. The medicinal product according claim 16, wherein theapplication of the administration form to the oral mucosa is selectedfrom the group consisting of sublingual application and buccalapplication.
 27. The medicinal product according to claim 14, whereinthe administration form is an administration form for application on theoral mucosa.
 28. The medicinal product according claim 27, wherein theapplication of the administration form to the oral mucosa is selectedfrom the group consisting of sublingual application and buccalapplication.
 29. A film-shaped, mucoadhesive administration formcontaining a cannabis agent selected from the group consisting ofcannabis extract and cannabis oil, wherein said administration formcomprises a polymer matrix, said polymer matrix being an activesubstance reservoir and having mucoadhesive properties, wherein saidadministration form contains said cannabis agent selected from the groupconsisting of cannabis extract and cannabis oil in an amount of 0.5 to50%-wt, and wherein the layer thickness is 0.01 to 2 mm.
 30. Theadministration form according to claim 29, wherein said polymer matrixcontains at least one polymer being water-soluble and/or swellable in anaqueous media, said at least one polymer is selected from the groupconsisting of starch and starch derivatives, dextran, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodiumcarboxymethyl cellulose, ethyl cellulose or propyl cellulose,polyacrylic acid, polyacrylates, polyvinyl pyrrolidones, polyethyleneoxide polymers, polyacrylamides, polyethylene glycol, gelatine,collagen, alginates, pectins, pullulan, tragacanth, chitosan, alginicacid, arabinogalactan, galactomannan, agar-agar, agarose, carrageenanand natural gums, and wherein said administration form comprises said atleast one polymer at a portion of 5 to 95%-wt.
 31. The administrationform according to claim 30, wherein said administration form has amultilayer structure with at least one layer having an active agentcontent.
 32. The administration form according to claim 29, wherein theadministration form is a film-shaped, mucoadhesive administration formcontaining a cannabinoid agent selected from the group consisting oftetrahydrocannabinol, cannabinol, cannabidiol and cannabichromen andwherein said administration form comprises a polymer matrix, saidpolymer matrix being an active substance reservoir and havingmucoadhesive properties.
 33. The medicinal product according to claim13, wherein said administration form comprises a polymer matrix, saidpolymer matrix being an active substance reservoir and havingmucoadhesive properties, said reservoir containing said active agentselected from the group consisting of tetrahydrocannabinol, cannabinol,cannabidiol and cannabichromen.